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C.V. Starr Laboratory of Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York
Address correspondence and reprint requests to Neil L. Harrison, PhD, Professor and Director, C.V. Starr Laboratory of Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY 10021. Address e-mail to neh2001{at}med.cornell.edu
In the last 3 years, we have witnessed exciting new developments in our understanding of anesthetic mechanisms. This editorial comments on the review by Sonner et al. (1) and describes recent key advances in the field.
In a recent commentary I drew attention to the growing perception of the importance of ion channels, especially 
-aminobutyric acid (GABA)-A and N-methyl-D-aspartic acid (NMDA) receptors, to general anesthetic mechanisms (2). Here I will first discuss the exhaustive review by Sonner et al. that appears within these pages (1), and will then describe the current state of excitement within the field. Finally, I note that many of the most critical recent observations were made in Europe, and that the U.S. research community may need to work hard to stay in the race.
Research on anesthetic mechanisms was stagnant for much of the 20th century, primarily because of the almost universal acceptance of the dogma of nonspecific anesthetic action—the so-called "Lipid Theory." In the 1960s and 70s, descriptions of general anesthetic action in the major textbooks recalled the story of the Emperor’s New Clothes—long on imagination, but transparently lacking in substance.
The overthrow of this dogma occurred slowly over the last two decades, with Nick Franks and his coworkers playing a central role, steadily chipping away at the foundations of the Lipid Theory (3–5). In many ways, this process resembled the Cold War—years of attrition, before the edifice collapsed and the Berlin Wall was dismantled over a few short days (this was perhaps most evident at a conference held in Calgary in 1997). A sign that the changes are being consolidated and "receptor-based" theories are now ascendant was the recent publication of perhaps the first modern and truly scientific description of anesthetic mechanisms within a major textbook (6).
Despite this, education remains an important priority within the field. I recently spoke at a department in which the senior faculty were unaware that glutamate was the fast excitatory neurotransmitter in the brain, but were apparently convinced that acetylcholine and norepinephrine performed the same roles in the central nervous system that they do in the autonomic nervous system.
Sonner et al. provide an extensive review of recent developments (1). This group, a multicenter research program based at the University of California, San Francisco (UCSF), has long pursued a highly collaborative and interactive strategy that centered around twice-yearly meetings at which a diverse group of investigators focuses intensely on novel issues and experiments. These gatherings have occurred outside of the framework of the traditional conferences, but bring together talented minds from around the world who share an interest in problems of general anesthetic action. Another successful anesthesia research group in St. Louis has adopted an equally successful, but more local approach, by interacting extensively with the strong basic science community at Washington University.
Sonner et al. present persuasive, but perhaps not completely definitive, arguments in favor of certain neurotransmitter receptors and ion channels as anesthetic targets, while eliminating others from consideration. The review focuses on the ability of general anesthetics to abolish purposeful movement in response to a noxious stimulus, an endpoint introduced by Eger and enshrined in the "MAC" concept (7,8). As they carefully point out, Sonner et al. ’s conclusions need not apply to other anesthetic end-points, such as hypnosis, amnesia and analgesia. Since I agree with much of what the authors have written, I do not intend to reprise their scholarly efforts here. I will instead highlight a few of those very recent experiments that I consider most likely to be influential in the near future.
Two seminal papers on anesthetic mechanisms appeared in 2002. First, Laura Nelson et al. (9), working in London and Boston, described the involvement of a small neuronal nucleus in the rat hypothalamus in the hypnotic actions of propofol and etomidate. Second, Rachel Jurd and her colleagues (10) in Zürich reported that a mouse engineered to harbor a specific point mutation in the gene encoding the ß-3 subunit of the GABA-A receptor is essentially insensitive to the immobilizing actions of propofol and etomidate.
Nelson et al., a team from Mervyn Maze and Nick Franks’ labs and Clifford Saper’s group, used stereotactic injections of the GABA-A receptor antagonist GABAzine to test the idea that specific brain nuclei contribute to the hypnotic actions of certain general anesthetics (9). Remarkably, they found that microinjections of GABAzine into the tuberomamillary nucleus (TMN) of the hypothalamus reversed the hypnotic actions of etomidate and propofol, but not those of ketamine, which acts primarily at NMDA receptors and not at GABA-A receptors.
This is a striking finding for three reasons. First, it documents a role for GABA in the actions of these IV anesthetics, secondly, it suggests that these anesthetics act locally rather than globally in the CNS, and third, it arouses fresh interest in the connections between sleep and anesthesia (11), since the TMN is part of an endogenous sleep control system. Combined with Sarah Tomlin et al.’s (12) crucial earlier paper on the stereospecific actions of etomidate’s optical isomers, these results appear to offer incontrovertible scientific proof of the involvement of specific populations of GABA-A receptors in producing several components of general anesthesia for these two IV anesthetics.
The Zürich group’s (10) result may be even more important. This group performed an experiment first proposed during the 1990s, after a series of landmark observations showing that specific point mutations could ablate the allosteric enhancing effects of anesthetics on the GABA-A receptor (13–15). These results implied that a mutant mouse could be constructed (a knock-in mouse) that could be used to assess the importance of an individual gene product in the action of general anesthetics.
Jurd et al. did just that (10). They introduced a mutation into the mouse gene encoding the beta-3 subunit of the GABA-A receptor. This resulted in replacement of a single asparagine residue with the amino acid methionine, a simple change that rendered the receptor insensitive to propofol and etomidate in vitro (15). The resulting knock-in mouse was >20 times less sensitive than its wild-type siblings to etomidate and propofol in measurements of withdrawal from tail clamp and loss of righting reflex (10). This stunning correspondence between in vitro and in vivo results proves the validity of the "GABA hypothesis" for the action of these two IV anesthetics and highlights the utility of the knock-in mouse technique. Indeed, the proof of principle for this was already shown by Lakhlani et al.’s (16) studies of dexmedetomidine in an 
-adrenoceptor knock-in mouse.
Given these recent advances in our understanding of the pharmacology of IV anesthetics, what about the inhaled anesthetics? As Sonner et al. (1) point out, the situation here is far less clear—for one thing, there appear to be several more viable anesthetic targets for the volatile drugs. For example, inhaled anesthetics modulate GABA-A receptors, inhibit NMDA receptors (17), activate "resting" potassium channels (18) and inhibit the cyclic nucleotide-regulated channels that underlie pacemaker currents in the brain (19). A consensus view, expressed by Sonner et al.(1), is that GABA-A receptors are perhaps less important to the actions of the inhaled anesthetics than is the case for propofol. There seems little doubt that additional knock-in and knock-out mice will appear soon, and that these animals will provide further insight into the mechanisms of inhaled anesthetic action.
An additional frontier in anesthesia research involves the study of anesthetic actions at the level of neuronal networks. Recent work from two groups in the U.K. has shown that high frequency "gamma oscillations" resulting from synchronous activity in cortical networks are sensitive to disruption by both IV and inhaled general anesthetics (20,21). These gamma oscillations are associated with cognitive activity and depend on GABA-mediated synaptic inhibition. Anesthetics that modulate GABA-A receptors all slow down and/or desynchronize gamma frequency (30–60Hz) activity.
So, these are exciting times. One might expect that U.S. anesthesia researchers would be alongside the Europeans in the pursuit of mechanisms for additional IV anesthetics and for those drugs that have been most mysterious in their actions – the inhaled anesthetics. It can only be hoped that the recent successes detailed by Sonner et al. will soon herald further insights. However, many of the discoveries now shaping our future understanding are being made by very large interactive groups in Europe. As the search for anesthetic target sites narrows and grows more heated, more and more of the most significant work is being done by large scientific teams, many of them outside of the U.S., principally in Switzerland and the United Kingdom.
The continuing support of anesthesia research by the National Institutes of Health (NIH) via the Program Project Group mechanism (for example, the UCSF and St Louis groups) seems to me to be a critical tool to enable U.S. scientists to continue to compete. The continued support and mentoring of young investigators is also crucial; in this context, one is reminded of the idea promoted during Harold Varmus’ tenure as NIH Director, that grant review panels should focus on the innovation and significance of proposals. The U.S. anesthesiology community should continue to heed this suggestion, or we may be forced to watch from the sidelines, as the Europeans pick up the ball and run with it.
References
-aminobutyric acid-A receptor distinct from that for isoflurane. Mol Pharm 1998; 53: 530–8.This article has been cited by other articles:
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  P. M Joksovic, D. A Bayliss, and S. M Todorovic Different kinetic properties of two T-type Ca2+ currents of rat reticular thalamic neurones and their modulation by enflurane J. Physiol., July 1, 2005; 566(1): 125 - 142. [Abstract] [Full Text] [PDF]
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 X. Chen, J. E. Sirois, Q. Lei, E. M. Talley, C. Lynch III, and D. A. Bayliss HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents J. Neurosci., June 15, 2005; 25(24): 5803 - 5814. [Abstract] [Full Text] [PDF]
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